The Impact of The FDA’s Recent Decision to Reject UX-111

Introduction to Sanfilippo

Sanfilippo Syndrome is a lysosomal storage disorder characterized by a deficiency in one of four

enzymes, which result in one of four types of Sanfilippo. Type A is associated with the enzyme

Heparan N-sulfatase, which Type B is associated with alpha-N-acetylglucosaminidase, which

Type C is associated with Acetyl CoA: alpha-glucosaminidase N-acetyltransferase, which and

Type D is associated with N-acetulglucosamine-6-sulfatase, which are all enzymes that perform a

crucial step in the breakdown of heparin sulfate. Deficiency of one of these enzymes cause a

buildup of heparin sulfate, which changes the function of enzymes that “clean up” the brain. As

waste accumulates in the brain due to the lack of these enzymes, it interferes with neural

pathways and neural cell signaling in the brain, which causes neurodegeneration (deterioration of

gray matter in the brain), and leads to cognitive decline. Sanfilippo is extremely difficult to

diagnose in its early stages, as the cognitive function delays can easily be mistaken for ADHD

and autism. By the time it is caught, it is often in the late stages, where mental and physical

decline is occurring exponentially. There is no current cure for Sanfilippo Syndrome, and many

clinical trials are currently being done to advance towards one.

However, one drug showed great promise in its early clinical stages, called UX-111. UX-111

presented their clinical findings at WORLDSymposium in February of 2025, showing that the

drug was beginning to show significant improvements in cognitive function in children with

Sanfilippo Syndrome. Unfortunately, on July 11 th , the US Food and Drug Administration (FDA)

rejected the drug due to experimental design issues and minor manufacturing issues. The delay

of this drug could set the implementation back an entire year. As of January 30 th , Ultragenyx is

still in the process of resubmitting the biologics license application.

Clinical Effectiveness of UX-111

The effectiveness of UX-111 was made clear in clinical trials, where the findings, put simply,

showed that this drug improved cognitive test scores by an average of 22.7 points, indicating a

clinically and statistically significant retention of fine motor skills in children with more

advanced diseases. Among the ten children in the study (between ages of 5.6 and 14.8), all 10

retained communication skills and 9 retained ambulation and the ability to eat/self-feed, which is

something that drastically declines with the progression of Sanfilippo. These findings

demonstrate the clinical success of this drug in improving Sanfilippo symptoms and function.

The FDAs Decision

According to the official website of Ultragenyx, the manufacturing company of UX-111, the

FDA issued a Complete Response Letter (CRL), asking the company to provide additional

information and improvements related to specific aspects and observations of Chemistry,

manufacturing and controls (CMC) and observations from the recently completed manufacturing

facility inspection. While the FDA rejected the drug due to these issues, they acknowledged the significance of the clinical data provided and its promise in improving symptoms caused by

neurodegenerative diseases, specifically Sanfilippo.

Ethical Considerations

The recent decision by the FDA provokes the question: should these minor manufacturing issues

be ignored for the sake of time? Children with Sanfilippo are typically only expected to live 10-

20 years after onset, and according to Karthik Kumar, MBBS, early stages of Sanfilippo are

often mistaken for autism, and it is not diagnosed until it is in later stages, where the decline is

exponential, which increases the pressure on finding an effective cure in a timely manner.

Sanfilippo is a very time sensitive disease. Within the year this drug will take to be implemented,

a child who was walking could be immobilized, someone who was talking could be mute, and

severe neurological deterioration could occur. In an interview with the mother of an anonymous

patient, she stated that in the last year, her son has lost significant ambulatory ability and ability

to talk, feed himself, and is now in a wheelchair when just a year ago, he was nearly fully

cognitively functioning.

In order to effectively release the treatment UX-111 to treatments, Ultragenyx and the FDA must

come to a solution to address the consequences on patient outcomes by minor manufacturing

issues in a timely manner.

Skylar Falkner studies Biomedical Engineering at the University of Virginia. She is passionate about neurodegenerative disease and hopes to attend medical school while exploring the intersection of medicine and biotechnology.

References

Ultragenyx Receives Complete Response Letter from FDA for UX111 AAV Gene Therapy to

Treat Sanfilippo Syndrome Type A (MPS IIIA)—Ultragenyx Pharmaceutical Inc. (2025).

Retrieved from Ultragenyx Pharmaceutical Inc. website: https://ir.ultragenyx.com/news-

releases/news-release-details/ultragenyx-receives-complete-response-letter-fda-ux111-

aav-gene

Ultragenyx Announces New Data Demonstrating that Treatment with UX111 AAV Gene

Therapy Significantly Improved Clinical Function Across Multiple Developmental

Domains in Children with Sanfilippo Syndrome Type A (MPS IIIA) Correlated with

Sustained Reductions in CSF-HS—Ultragenyx Pharmaceutical Inc. (2025). Retrieved

November 18, 2025, from Ultragenyx Pharmaceutical Inc. website:

https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-new-

data-demonstrating-treatment-ux111-aav

(Interview with Mother of Anonymous Patient, 2025)

Sanfilippo Syndrome: What It Is, Symptoms & Treatment. (2024, July 24). Retrieved from

Cleveland Clinic website: https://my.clevelandclinic.org/health/diseases/sanfilippo-

syndrome